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Characterisation of insulin analogues therapeutically available to patients
#MMPMID29596514
Adams GG
; Meal A
; Morgan PS
; Alzahrani QE
; Zobel H
; Lithgo R
; Kok MS
; Besong DTM
; Jiwani SI
; Ballance S
; Harding SE
; Chayen N
; Gillis RB
PLoS One
2018[]; 13
(3
): e0195010
PMID29596514
show ga
The structure and function of clinical dosage insulin and its analogues were
assessed. This included 'native insulins' (human recombinant, bovine, porcine),
'fast-acting analogues' (aspart, glulisine, lispro) and 'slow-acting analogues'
(glargine, detemir, degludec). Analytical ultracentrifugation, both sedimentation
velocity and equilibrium experiments, were employed to yield distributions of
both molar mass and sedimentation coefficient of all nine insulins. Size
exclusion chromatography, coupled to multi-angle light scattering, was also used
to explore the function of these analogues. On ultracentrifugation analysis, the
insulins under investigation were found to be in numerous conformational states,
however the majority of insulins were present in a primarily hexameric
conformation. This was true for all native insulins and two fast-acting
analogues. However, glargine was present as a dimer, detemir was a
multi-hexameric system, degludec was a dodecamer (di-hexamer) and glulisine was
present as a dimer-hexamer-dihexamer system. However, size-exclusion
chromatography showed that the two hexameric fast-acting analogues (aspart and
lispro) dissociated into monomers and dimers due to the lack of zinc in the
mobile phase. This comprehensive study is the first time all nine insulins have
been characterised in this way, the first time that insulin detemir have been
studied using analytical ultracentrifugation and the first time that insulins
aspart and glulisine have been studied using sedimentation equilibrium. The
structure and function of these clinically administered insulins is of critical
importance and this research adds novel data to an otherwise complex functional
physiological protein.
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